Katie Falloon, MD

As more advanced therapies are approved for the treatment of inflammatory bowel disease (IBD), insights into optimal positioning of therapies have grown increasingly important. The new phase 3b SEQUENCE study offers randomized controlled trial data comparing efficacy and safety of 2 medications approved for moderate to severe Crohn’s disease (CD), ustekinumab and risankizumab. Both act by blocking cytokine signaling that plays an important role in CD pathogenesis. Ustekinumab, the first available medication of this class, blocks the cytokines interleukin-12 (IL-12) and IL-23. Risankizumab, on the other hand, selectively blocks only IL-23. Following initial loading with an intravenous formulation (one intravenous dose for ustekinumab and three intravenous doses for risankizumab), both are given subcutaneously for maintenance dosing. Of note, maintenance risankizumab is administered via an on-body injector.

To be included in the SEQUENCE study, patients needed to be diagnosed with moderate to severe CD refractory to ≥1anti-tumor necrosis factor (TNF) medication such as infliximab or adalimumab. For the purposes of this study, moderate to severe CD was defined clinically as a CD activity index (CDAI) of 220-450 with ≥4 bowel movements per day and/or moderate to severe abdominal pain and was defined endoscopically as a Simple-Endoscopic Score for CD of ≥6 excluding the narrowing component (≥4 for isolated ileal disease). Endoscopy reports were scored by the site investigator with confirmation by a central reader, who was blinded to the study treatment.

Patients were randomized in a 1:1 fashion to either risankizumab (n = 255) or ustekinumab (n = 265). With respect to baseline demographics and disease characteristics, mean age was 38 years, approximately 50% of patients were female, mean disease duration was 9.4 years, approximately 22-26% of patients were on corticosteroids, and disease location was a mix of ileal (approximately 17%), colonic (40%), and ileocolonic (43%).

Primary endpoints were CDAI remission at week 24 and endoscopic remission at week 48. Secondary endpoints include endoscopic remission at week 24, clinical and endoscopic remission at week 48, and steroid-free clinical and endoscopic remission at week 8.

Risankizumab demonstrated non-inferiority to ustekinumab for clinical remission at week 24 (59% of patients on risankizumab were in clinical remission compared to 39.5% of patients on ustekinumab), and statistically significant superiority to ustekinumab for endoscopic remission at week 48 (31.8% of patients in remission on risankizumab compared to 16.2% of patients on ustekinumab). With respect to secondary endpoints, risankizumab demonstrated superiority across all recorded endpoints. There were no notable differences with respect to rates of treatment emergent adverse events and risankizumab had numerically fewer patients with adverse events of special interest during the study period, such as opportunistic infections or injection site reactions.

Overall, this was a well-designed study that provides key insights regarding positioning of risankizumab versus ustekinumab. Applicability to patients who do not meet the inclusion criteria (for example, patients naïve to biologic therapy) is more limited, but certainly in patients with inflammatory CD refractory to anti-TNF agents the data suggests it makes sense to position risankizumab over ustekinumab. Cost and insurance coverage unfortunately may be potential barriers to this, in which case whichever therapy is most accessible to the patient should be the one prescribed. Of note, ustekinumab is currently the only anti-interleukin therapy approved for the treatment of ulcerative colitis (UC), but given the superior performance of risankizumab in CD patients, it will be interesting to see data regarding its efficacy in UC.

AbbVie. AbbVie's SKYRIZI® (risankizumab) Versus STELARA® (ustekinumab) Head-to-Head Study in Crohn's Disease Meets All Primary and Secondary Endpoints. Press Releases. October 15, 2023. Accessed October 16, 2023. https://news.abbvie.com/article_display.cfm?article_id=12621

Clinicaltrials.gov. Study Comparing Intravenous (IV)/​Subcutaneous (SC) Risankizumab to IV/​SC Ustekinumab to Assess Change in Crohn's Disease Activity Index (CDAI) in Adult Participants With Moderate to Severe Crohn's Disease (CD) (SEQUENCE). September 28, 2023. Accessed October 16, 2023. https://www.clinicaltrials.gov/study/NCT04524611

Articles

Ustekinumab is currently the only anti-interleukin therapy approved for the treatment of ulcerative colitis, but given the superior performance of risankizumab in CD patients, it will be interesting to see data regarding its efficacy in UC.

SEQUENCE: Comparing Risankizumab to Ustekinumab in Crohn’s Disease

 (IBD) is characterized by inflammation of the gastrointestinal tract, a significant proportion of patients with IBD suffer from a 

These complications, called extra-intestinal manifestations, are found in as many as half of all patients with IBD and yet have received only limited research attention, particularly in the US. 

This is problematic, as EIMs significantly impact patients’ quality of life, are associated with increased morbidity, and often require complex decision making and multi-specialty collaboration on the part of healthcare providers.

Due the heterogeneity in the literature and the lack of clear EIM definitions, we sought to standardize diagnostic, follow-up and treatment targets for 5 major EIMs (peripheral arthritis, axial arthritis, pyoderma gangrenosum, erythema nodosum, and uveitis).

To do this, we convened a modified Delphi consensus panel consisting of 12 gastroenterologists, 4 rheumatologists, 3 ophthalmologists, 6 dermatologists, and 4 patient representatives. 

The modified Delphi consensus methodology is an evidence-based approach that incorporates both previously published evidence and clinical expertise in order to arrive at answers to research questions.

Following literature review, development of candidate items, lively debate, and 3 voting rounds, we arrived at consensus criteria for appropriate and, when possible, optimal means of diagnosing and monitoring the 5 EIMs in question

The results provide guidance for the practicing clinician on items essential to management of EIMs, such as which provider should clinically diagnose each EIM and how frequently patients should be seen based on type and severity of EIM.

For example, uveitis can be vision threatening and requires ophthalmology involvement in diagnosis and monitoring with close follow-up, while erythema nodosum, which often self resolves, can be managed by either a gastroenterologist or a dermatologist and requires less intensive follow-up.

The results also standardize concepts that are essential to successfully conducting further research in this area, for example by outlining multi-specialty approved strategies to assess for improvement or worsening of each of the 5 EIMs, which is critical to determining if a given therapy is working effectively.

The results of our work were published in 

 early this year and are summarized in the table provided (Table 1).

Table 1. Extraintestinal Manifestation Definitions

I am excited to continue to build upon this work and move forward with further exploration of EIMs in IBD. With funding support from the Crohn’s and Colitis Foundation, we have built a network of 11 centers across the country and are creating a prospective registry of patients with EIMs (entitled CHASE-EIM [Cohort for Healing Arthritis, Skin, and Eye Extra-Intestinal Manifestations]) utilizing the definitions we developed. 

Initially we will focus solely on peripheral arthritis, which while the most common EIM is also arguably one of the least well-understood.

We are recruiting 100 patients across our network and following them for the course of 1 year. We will collect both objective measures of disease and EIM activity as well as patient reported outcomes via clinic visits and regular surveys. 

In so doing, we hope to better understand the overall clinical presentation of peripheral arthritis, investigate response to various therapies (both for IBD and for peripheral arthritis specifically), and clarify risk factors for development, progression, and recurrence of peripheral arthritis.

Investigators from the Cleveland Clinic standardized diagnostic, follow-up, and treatment targets for 5 major EIMs: peripheral arthritis, axial arthritis, pyoderma gangrenosum, erythema nodosum, and uveitis.

